tbuckley/cabot-search huggingface dataset:
Kidney Angiotensin in Cardiovascular Disease: Formation and Drug Targeting
Authors: Hui Lin, Frank Geurts, Luise Hassler, Daniel Batlle, Katrina M. Mirabito Colafella, Kate M. Denton, Jia L. Zhuo, Xiao C. Li, Nirupama Ramkumar, Masahiro Koizumi, Taiji Matsusaka, Akira Nishiyama, Martin J. Hoogduijn, Ewout J. Hoorn, A.H. Jan Danser
Journal: Pharmacological Reviews (2022)

The concept of local formation of angiotensin II in the kidney has changed over the last 10–15 years. Local synthesis of angiotensinogen in the proximal tubule has been proposed, combined with prorenin synthesis in the collecting duct. Binding of prorenin via the so-called (pro)renin receptor has been introduced, as well as megalin-mediated uptake of filtered plasma-derived renin-angiotensin system (RAS) components. Moreover, angiotensin metabolites other than angiotensin II [notably angiotensin-(1-7)] exist, and angiotensins exert their effects via three different receptors, of which angiotensin II type 2 and Mas receptors are considered renoprotective, possibly in a sex-specific manner, whereas angiotensin II type 1 (AT<sub>1</sub>) receptors are believed to be deleterious. Additionally, internalized angiotensin II may stimulate intracellular receptors. Angiotensin-converting enzyme 2 (ACE2) not only generates angiotensin-(1-7) but also acts as coronavirus receptor. Multiple, if not all, cardiovascular diseases involve the kidney RAS, with renal AT<sub>1</sub> receptors often being claimed to exert a crucial role. Urinary RAS component levels, depending on filtration, reabsorption, and local release, are believed to reflect renal RAS activity. Finally, both existing drugs (RAS inhibitors, cyclooxygenase inhibitors) and novel drugs (angiotensin receptor/neprilysin inhibitors, sodium-glucose cotransporter-2 inhibitors, soluble ACE2) affect renal angiotensin formation, thereby displaying cardiovascular efficacy. Particular in the case of the latter three, an important question is to what degree they induce renoprotection (e.g., in a renal RAS-dependent manner). This review provides a unifying view, explaining not only how kidney angiotensin formation occurs and how it is affected by drugs but also why drugs are renoprotective when altering the renal RAS. <h3>Significance Statement</h3> Angiotensin formation in the kidney is widely accepted but little understood, and multiple, often contrasting concepts have been put forward over the last two decades. This paper offers a unifying view, simultaneously explaining how existing and novel drugs exert renoprotection by interfering with kidney angiotensin formation.
Abstract 2003: Poor diet quality is associated with immune aging in survivors of pediatric acute lymphoblastic leukemia
Authors: Abderrahim Benmoussa, Tibila Kientega, Sophia Morel, Guillaume Cardin, Sophie Bérard, Mickael wajnberg, Petko Valtchev, Alexandre Blondin-Masse, Daniel Curnier, Maja Krajinovic, Caroline Laverdière, Daniel Sinnett, Emile Levy, Sophie Marcoux, Francis Rodier, Valérie Marcil
Journal: Cancer Research (2022)

Abstract Rationale and objectives: Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. Despite a 90% five-year survival rate, survivors of childhood ALL often suffer from late effects, including cardiometabolic disorders. Contributing factors such as inflammation and oxidative stress, combined with drug treatments, can induce premature aging and cellular senescence with a significant impact on cardiometabolic disorders. Premature aging can lead to decreased thymic T-cell production, resulting in decreased circulation of T-cell receptor excision circles (TRECs). Because diet has been associated with cardiometabolic disorders, we hypothesized that the quality of diet in children who had survived ALL was related to the immune aging biomarker TREC, in concert with inflammatory status. Methods: Adolescent and young adult survivors of pediatric ALL of the PETALE cohort (n=241, 22.1 ± 6.3 years at diagnosis, 49.4% male) were examined in their profile for TREC levels (by qPCR) and for adherence to 6 diet quality indices. Results: Adjusted linear regressions revealed that the Healthy Diet Indicator (HDI) was associated with TREC levels (β=50.0, p=0.005, adjusted p=0.03). After performing a conceptual relational analysis (CAR) for data mining of various biomarkers of inflammation, oxidative stress, endotoxemia, and endothelial or adipose dysfunction; interleukin-6 (IL-6) and C-reactive protein (CRP) were found to be negatively associated with TREC levels (β= -80 and -80.1, p=0.017 and 0.026, respectively) but not with HDI. Further analysis revealed that IL-6 and CRP levels were moderators, but not mediators, of the association between HDI and TREC. Conclusion: This study supports the positive impact of a healthy diet on premature immune aging and the moderating role of inflammation in this association. Citation Format: Abderrahim Benmoussa, Tibila Kientega, Sophia Morel, Guillaume Cardin, Sophie Bérard, Mickael wajnberg, Petko Valtchev, Alexandre Blondin-Masse, Daniel Curnier, Maja Krajinovic, Caroline Laverdière, Daniel Sinnett, Emile Levy, Sophie Marcoux, Francis Rodier, Valérie Marcil. Poor diet quality is associated with immune aging in survivors of pediatric acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2003.
Abstract 1758: The preclinical pharmacology of PRO1102, a novel exatecan-based HER2-directed antibody-drug conjugate with robust anti-tumor activity
Authors: Lei Wang, Haidong Liu, Xiao Shang, Tae H. Han, Baiteng Zhao
Journal: Cancer Research (2022)

Abstract PRO1102 is an antibody-drug conjugate (ADC) directed toward HER2, a validated protein target that is overexpressed in multiple cancers, including breast and gastrointestinal cancer. PRO1102 is comprised of 1) trastuzumab, a clinically and commercially validated HER2-directed antibody, 2) a cleavable, hydrophilic linker, and 3) exatecan, a topoisomerase 1 inhibitor. The mechanism of action and the clinical potential of PRO1102 was evaluated in a series of experiments. PRO1102 maintained the same binding attributes of the parent antibody, trastuzumab, in vitro. In mouse xenograft studies, PRO1102 demonstrated robust anti-tumor activity across multiple HER2-expressing cell lines that was generally better than ADCs with alternative drug-linker technologies, such as those associated with monomethyl auristatin E, mertansine (DM1) and deruxtecan. In addition, PRO1102 retained activity in cancer cells with moderate and low HER2 expression, suggesting the potential to benefit a broader range of patients of HER2-expressing cancers. The pharmacokinetics of PRO1102 was evaluated in rats and PRO1102 was stable in circulation with disposition similar to the parent antibody. Tolerability was evaluated in mice and at PRO1102 dose levels associated with robust anti-tumor activity, PRO1102 was well tolerated. PRO1102 exhibits the attributes needed for an effective ADC with robust activity in a broad selection of HER2-expressing cancers. Citation Format: Lei Wang, Haidong Liu, Xiao Shang, Tae H. Han, Baiteng Zhao. The preclinical pharmacology of PRO1102, a novel exatecan-based HER2-directed antibody-drug conjugate with robust anti-tumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1758.
Abstract 114: Progesterone via integrin αvβ3 induces cell proliferation in PR-negative breast cancer cells
Authors: Hung-Yun Lin, Tung-Yung Huang, Tung-Cheng Chang, Han-Yu Chen, Haw-Ming Huang, Sheng-Yang Lee, Zi-Lin Li, Hung-Ru Chu, Jacqueline Whang-Peng, Kuan Wang
Journal: Cancer Research (2022)

Abstract Background: Progesterone (P4) stimulates reproductive functions such as ovulation and the initiation and maintenance of pregnancy. P4 regulates biological activities via its nuclear receptor. However, it is not fully understood mechanisms involved in P4 functions in PR-negative cells. Anchor protein integrin αvβ3 plays a vital role in cancer growth and metastasis. Methods: We investigated the effect of P4 in PR-positive breast cancer MCF-7 cells and PR-negative breast cancer MDA-MB-231 cells. The protein and RNA expression changes induced by P4 were both analyzed in two cell lines. At the same time, the anti-integrin αvβ3 antibody and RGD peptide were employed for investigating the role of integrin αvβ3 in P4 regulation. Results: P4 inhibited the proliferation in MCF-7 cells but stimulated cell growth in MDA-MB-231 cells. In addition to ERK1/2 activation, P4 stimulated the phosphorylation at Y397 and Y925 in focal adhesion kinase (FAK), a vital kinase in integrin ανβ3 signal pathway that modulated by co-treatment with anti-integrin αvβ3 antibody or RGD peptide. P4 activated the gene expression of integrin ανβ3, CCND1, PCNA, and MMP-9 in MDA-MB-231 cells. P4 also induced PD-L1 and CCND1 accumulation. Conclusions: Progesterone via integrin αvβ3-mediated signal transduction regulates gene expression, cell proliferation, and migration in TNBC cells. It is the first time to demonstrate that P4 binds with the cell surface anchor protein, integrin αvβ3, to stimulate cancer cell proliferation in PR-negative breast cancer cells. Keywords: Progesterone, Progesterone receptor, Integrin αvβ3, Breast cancer, Cell proliferation Citation Format: Hung-Yun Lin, Tung-Yung Huang, Tung-Cheng Chang, Han-Yu Chen, Haw-Ming Huang, Sheng-Yang Lee, Zi-Lin Li, Hung-Ru Chu, Jacqueline Whang-Peng, Kuan Wang. Progesterone via integrin αvβ3 induces cell proliferation in PR-negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 114.
Abstract 789: Elucidating transcriptional dynamics in neuroendocrine differentiation of advanced prostate cancer
Authors: Chia-Chun Chen, Kai Song, Wendy Tran, Matthew Obusan, Tyler Sugimoto, Katherine Sheu, Donghui Cheng, Grigor Varuzhanyan, Liang Wang, Lisa Ta, Zhiyuan Mao, Nathanael Bangayan, Jung-Wook Park, Thomas Graerber, Owen Witte
Journal: Cancer Research (2022)

Abstract Small cell carcinomas of the lung, bladder, and prostate share similar transcription patterns and drug sensitivities. Due to their high cellular plasticity, these cancers often escape treatment through a trans-differentiation from adenocarcinoma to the neuroendocrine state. We previously developed a pan small cell cancer in vitro/in vivo model named PARCB that can recapitulate this transition from primary patient tissues. To understand which transcription factors may be important in this transition, we conducted bulk and single cell RNA sequencing over time. We identified a developmental trajectory that is shared among all samples and is defined by stage-specific transcription factors. We plan to interrogate the role that these transcription factors play in the PARCB transformation assay. We performed ATAC sequencing to investigate how these transcription factors regulate these transitional states. Our study will provide a basic understanding of the transcriptional changes that occur during neuroendocrine differentiation and provide new potential therapeutic targets for small cell cancers. Citation Format: Chia-Chun Chen, Kai Song, Wendy Tran, Matthew Obusan, Tyler Sugimoto, Katherine Sheu, Donghui Cheng, Grigor Varuzhanyan, Liang Wang, Lisa Ta, Zhiyuan Mao, Nathanael Bangayan, Jung-Wook Park, Thomas Graerber, Owen Witte. Elucidating transcriptional dynamics in neuroendocrine differentiation of advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 789.
Abstract 6287: Comparison of multiple myeloma provider for Black Americans and Caucasian Americans
Authors: Christian S. Cheung, Nathan W. Sweeney, Zena M. Tiu, Cynthia Chmielewski, Jennifer M. Ahlstrom
Journal: Cancer Research (2022)

Abstract Background: Although Black Americans have 2-3 times multiple myeloma (MM) incidence and mortality as compared to Whites, increasingly research is demonstrating that many may have genetic characteristics that have better survival outcomes. Yet delayed diagnoses and inappropriate first lines of therapy often wipe out whatever “advantages” they may have had, keeping mortality statistics higher than would be expected (PMID: 25469920). For underserved populations, a number of commonly accepted disparities exist in myeloma, and more broadly, cancer care. Patients who receive treatment by a high-volume provider (myeloma specialist) is a factor that can help patients with MM to have a longer life expectancy (PMID: 31487686). Therefore, we analyzed whether there is a disparity between race and receiving care from a myeloma specialist which may contribute to the differences in survival that is being seen. Methods: Validated real-world (RW) MM patient data was collected through HealthTree Cure Hub for Multiple Myeloma (healthtree.org). We examined the patient’s race which was either Caucasian American or Black American and whether or not they were being treated by a myeloma specialist. The association between race and specialist was examined by a chi-squared (X2) test. Results: In this retrospective analysis of 2,871 MM patients, we compared Caucasian Americans (n= 2716) and Black Americans (n=155). Our analysis revealed a significant association between the two races and whether or not they had a myeloma specialist, X2(1, N = 2,871) = 5.85, p = 0.015. Black Americans were less likely to be treated by a myeloma specialist. Conclusion: The findings of this RW analysis identify a glaring disparity in Black American MM patients and receiving care from a myeloma specialist. Addressing the underlying cause of the findings could extinguish other MM-related issues, such as delays in getting a correct diagnosis, lack of access to myeloma specialists, and many other non-medical issues leading to less-than-optimal outcomes from the majority of these Black American patients. Citation Format: Christian S. Cheung, Nathan W. Sweeney, Zena M. Tiu, Cynthia Chmielewski, Jennifer M. Ahlstrom. Comparison of multiple myeloma provider for Black Americans and Caucasian Americans [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6287.
Abstract 139: Dock7 regulates the AKT/mTOR pathway to promote survival and sustain the transformative properties of cancer cells
Authors: Oriana Y. Teran, Miao-chong J. Lin, Matthew R. Zanotelli, Kristin F. Wilson, Richard A. Cerione
Journal: Cancer Research (2022)

Abstract Akt is a well-known target of mitogenic signaling, which is activated by phosphoinositide 3-kinase, PDK1 and mTORC2, and is commonly regarded as a master regulator of cell survival. However, there is still a good deal to learn regarding how Akt can promote survival when cancer cells are faced by the multitude of challenges they need to overcome during the process of malignant transformation. While investigating the role of Dock7, a Cdc42 and Rac guanine nucleotide exchange factor of the Dock180 family, in tumorigenesis, we discovered an unexpected connection between Dock7, Akt and cell survival. Specifically, we found that Dock7 is necessary for cancer cells to survive under the stressful conditions that arise due to the loss of a substratum or serum deprivation, through its ability to stabilize a low, basal level of Akt kinase activity. Dock7 binds to Akt, as well as associates with the known Akt substrate, TSC2, promoting its phosphorylation. Since the phosphorylation of TSC2 eliminates its ability to work with its partner TSC1 to deactivate the Rheb GTPase, a direct activator of mTORC1, we probed whether mTORC1 function is also necessary for Dock7-dependent cancer cell survival. Indeed, we determined that Dock7, as well as its signaling partner Cdc42, is required to maintain a functional level of S6 kinase activity, a downstream target of mTORC1, which was prevented by the mTORC1 inhibitor rapamycin. We further show an association between mTOR, Rheb and Dock7, but not Raptor, the defining component of mTORC1. Additionally, Raptor is dispensable for the Dock7-dependent S6 kinase activity, despite its rapamycin sensitivity. Together, these findings elucidate a novel Dock7-Akt-mTOR signaling node which promotes cancer cell survival in the absence of classical mTORC1 function to allow cells to overcome stresses faced during the development of cancer. Citation Format: Oriana Y. Teran, Miao-chong J. Lin, Matthew R. Zanotelli, Kristin F. Wilson, Richard A. Cerione. Dock7 regulates the AKT/mTOR pathway to promote survival and sustain the transformative properties of cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 139.
Abstract 6024: Developing a panel of orthotopic syngeneic tumor models for IO drug discovery
Authors: Gaoxiang Liu, Quanhong Sun, Wenting Shi, Qingyang Gu, Qunsheng Ji
Journal: Cancer Research (2022)

Abstract Immuno-oncology (IO) therapy is the focus of drug discovery in recent years. Unlike chemotherapy or targeted agents, the pharmacological efficacy of immune-oncology therapies needs to be evaluated in animal models with functional immune system. Syngeneic tumor models are established by inoculating mouse cancer cell lines to immunocompetent mice with the same genetic background. The host mice have complete immune activity and show histocompatibility with homograft tumor tissues, which can maximize the simulation of the real tumor microenvironment. Subcutaneous syngeneic models are easily established and have been widely used; however, the subcutaneous tumors lack organ-specific stromal-tumor interactions that are critical for disease progression in patients. Orthotopic tumor models are established in organ-specific sites, facilitating metastatic spread, supporting immune and stromal component interactions, and providing a more disease-relevant tumor microenvironment for IO therapy assessment. In order to facilitate the development of IO drug, we have established a panel of orthotopic syngeneic tumor models. We generated a series of luciferase-labeled bioluminescent mouse tumor cell lines, which were then engrafted into the organ of interest to establish orthotopic models. Bioluminescent imaging (BLI) enabled non-invasive in vivo imaging of orthotopic tumor burden, the real time tumor growth, and the response to therapies, monitored by quantitative bioluminescent signals. Overall, these established orthotopic syngeneic tumor models recapitulate the clinically relevant tumor microenvironment and serve as a useful tool in the pre-clinical evaluation of immunotherapies. Citation Format: Gaoxiang Liu, Quanhong Sun, Wenting Shi, Qingyang Gu, Qunsheng Ji. Developing a panel of orthotopic syngeneic tumor models for IO drug discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6024.
Abstract 2176: NADPH production and redox homeostasis regulate acinar to ductal metaplasia
Authors: Megan D. Radyk, Barbara S. Nelson, Christopher J. Halbrook, Mengrou Shan, Jonathan Alektiar, Howard C. Crawford, Yatrik M. Shah, Costas A. Lyssiotis
Journal: Cancer Research (2022)

Abstract Activating mutations in KRAS reprogram cellular metabolism to support continuous growth, proliferation, and survival in pancreatic cancer. However, there is little information on how KRAS-dependent alterations in metabolism change precancerous states and cancer initiation. Acinar cells can give rise to pancreatic tumors through acinar-to-ductal metaplasia (ADM), a reversible cell state that persists and progresses to neoplasia and cancer with oncogenic KRAS. During ADM, acinar cells transdifferentiate to duct-like cells, a process we hypothesized was mediated by metabolic rewiring. We performed transcriptomic analysis on acinar cells undergoing ADM and found metabolic programs are globally enhanced. Indeed, we and others have demonstrated how inhibiting metabolic pathways necessary for ADM can prevent transdifferentiation and tumorigenesis. A detailed analysis of our data revealed that the transcripts for NADPH-producing enzymes, Glucose-6-phosphate dehydrogenase (G6pd) and Malic enzyme 1 (Me1), were significant enriched during ADM. Following these results, we obtained G6pd-mutant mice and generated Me1flox/flox mice and bred them into the KC (KrasLSL-G12D/+;Ptf1aCre/+) line, resulting in KCG (KrasLSL-G12D/+;Ptf1aCre/+;G6pdmut/mut) and KCM (KrasLSL-G12D/+;Ptf1aCre/+;Me1flox/flox) mice. Interestingly, KCG and KCM mice develop ADM and neoplasia faster than their KC counterparts. We also observe that acinar cells and ADM in KCG cells have higher levels of lipid peroxidation and reactive oxygen species (ROS) both in vivo and using primary ex vivo acinar cell cultures. Thus, increased ROS levels may underlie ADM acceleration in this system. In primary acinar cell culture, we can rescue the accelerated ADM phenotype in KCG cells with the addition of antioxidants. Furthermore, we find that treatment of wild type acinar cells with buthionine sulphoximine (BSO) to deplete glutathione levels and increase ROS also accelerates ADM in culture. These results suggest that NADPH and glutathione pools are important for regulating redox levels during ADM, and that reducing these pools leads to accelerated tumorigenesis. Together, this work demonstrates new metabolic pathways driving pancreatic cancer initiation. Citation Format: Megan D. Radyk, Barbara S. Nelson, Christopher J. Halbrook, Mengrou Shan, Jonathan Alektiar, Howard C. Crawford, Yatrik M. Shah, Costas A. Lyssiotis. NADPH production and redox homeostasis regulate acinar to ductal metaplasia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2176.